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Anxiety, Obsessive Compulsive Disorder, Microglia, From Being a WWII Orphan to the Nobel Prize

Full auto-generated transcript below. Beware of typos & mistranslations!

Mario Capecchi 5:24

Mario Capecchi, I'm a professor at University of Utah. And I've been there forever. And mainly do research and some teaching. Research is one of the properties of my research is that every 10 years, I change subjects completely. And that's a real transformation in the sense not only the information content, but also social content. For example, we go to meetings, and I use need an entirely new people, because he's not working on cancer, which was what we were just previously working on. And now we're in neurobiologist. And so we talking about the neuroscientists. And these, I enjoy that process. And I've done it literally every 10 years or so, my whole career. And I think there's not a sense, it's important, because I'm naive. I don't know the questions I should be asking. And I go into a crowd. And then first of all, you always have to start at the bottom and you work your way up. So it's, it's a rejuvenating process, that the thing because it's a, you know, your mind loves to be challenged. And as long as you challenge it, it's active. And if you don't challenge it, then it goes asleep.

Nick Jikomes 6:47

And so is that is that like a conscious choice to switch fields after a number of years, okay, so it's not, I look

Mario Capecchi 6:55

ahead and think about where I want to go next, and then often teach a course in it. So I really have to look into the literature and the, you know, be able to talk to students. And then and then from then on for 10 years. I'll stick with it. Right now. We're year three of the recites.

Nick Jikomes 7:15

Wow. So you're doing so you're you're most well known for your work in molecular biology and genetics. And I definitely want to ask you about some of that. But you're in neurobiology. Now. What what's like, what kind of questions? Are you asking what's exciting? Working on? We're primarily working on two neuropsychiatric disorders, anxiety, and OCD. And they often occur together.

Mario Capecchi 7:38

That is in in our mice, it's 100%. In humans, it's about 80%.

So it's, and the question is, why it to the way of working together, what is, and we've, you know, by we also buy a new technology. So I'm very technology centered, having developed technology, and then having to utilize, and you know, most people are not comfortable changing. But the science actually, you have to change. It's absolutely demanding. And I think one of the things that happens is that influence a new technology, and then everybody's excited about it, and utilize it and see what happens with it. And in some times, you get a lot of surprises, for example, optogenetics has been around for a while. But nobody's ever done optogenetics in cells other than neurons. And so we decided to work out a population that isn't nice, but here are in the brain. They're called microglia, the immune cells of the spring. And, to our surprise, we activate microglia in specific regions of the brain, we turn on behaviors, we turn off the light, laser, and then the behavior stops. So so we, so these

Nick Jikomes 8:59

are, these are the immune cells of the brain. So they don't, they don't fire action potentials like neurons. That's right. They're like white blood cells, you turn them on, you get behaviors, what kind of behaviors

Mario Capecchi 9:10

and in this case, anxiety and OCD. And that's why we're studying those. And and the other thing we've discovered, I mean, the dogma was that there's only a single population of microglia. And we come along and say, well, maybe I think there's a second population. And, and there's resistance, obviously, God, there used to work population that don't want to think about two populations. But all of a sudden, not only is the two populations, but actually you should have we should have anticipated you need two populations. I mean, biology wouldn't have it if it doesn't need it. And the question is, oh, why do you have two populations and they turn up they work in opposition to each other, not in parallel? One of them increases the behavior, the other decreases the behavior. And then together, they can now set a new setpoint depending on the conditions that are in the environment, so it allows them a very sensitive system to be able to shift the level of anxiety, both groups, what we see as OCPs of overgrowing pathological movie, the mice continues to grow until they actually have lacerations. And both behaviors are dependent on essentially microbial controlling them. Obviously, they're not the neurons are controlling all the actual B hitmaking behavior, but the microglia are talking to, and then controlling the level of behavior output.

Nick Jikomes 10:47

We know how they're actually doing that. So how are they actually modulating neural activity?

Mario Capecchi 10:53

That we don't know, we don't know that no one's talking to yet. That's the next step. I mean, right now, we know they're talking but we don't know the conversation. And we don't know, for example, is it like, again, so is it direct electrical contacts, because you know, all cells have, essentially, membrane potentials. And they can Na, and their membrane potential can change with influx of ions. And here, if we use optogenetics, to pump it in terms of light, then we're affecting their behavior, and changing the output of the bar microglia, which then thought to neurons, and then they respond, and we're interested in in that conversation, we're just setting up the tools to be able to measure that compensation.

Nick Jikomes 11:40

And so you're so you're still, you're still going into lab every day, and you're still doing

Mario Capecchi 11:46

well, at full, full 100%.

Nick Jikomes 11:49

So how much of that is just, you know, what sort of what keeps for those who don't know, and we'll talk about this, you know, you're you're in your mid 80s, you've won the Nobel Prize, you've sort of done at all, so to speak, is what what's keeping you going in every day for such a difficult job?

Mario Capecchi 12:05

I think, curiosity? I mean, I think what, you know, when you see something completely unexpected, then you have an AHA period. And that's, you know, that's a rush it was, and it's fun. And I think that's, essentially, I'm not out to prove anything now. I simply enjoy the science. And, and, you know, it's almost like a confrontation between nature and yourself. She knows how everything's happening. And you don't, you can see what she's doing. But you have no idea how she's doing it. And so then the question is, you know, how can we figure that out? And then eventually, can we use it them to actually help in the sense of, you know, anxiety is a enormous problem, especially right now, me COVID has just raised the roof. And it's just rampant all over the world. And now we have, and the other thing you will notice has to keep in mind is a little anxiety is fantastic. It keeps you you know, keeps you cool, focused, such as it allows you to pursue something rather than it be distracted. Similarly, with grooming, small amounts of grooming, gratifying but pathological ones, which lead to lacerations is pathology. So it's important to have the right level of both behaviors at the right time, depending on what's happening in the outside world, relative to yourself.

Nick Jikomes 13:31

And so, you know, you just You said you'd like to, to decide to switch fields, you know, every 10 years or so, you've gotten into neurobiology, you're studying microglia and how they impact the nervous system in the context of OCD and anxiety. How did you pick that field as opposed to just some other area of neuroscience?

Mario Capecchi 13:50

Well, one stage state, we worked in developmental biology and enter into cancer biology and then into neurobiology. When I was in developmental biology, we're interested in a group of gene called HOX genes. And they're involved in specifying the body plant and make sure I had this here, the arms are the right place, and all the organs in the right place, so and so coordination system, but we're not that one gene. And rather than getting some change in body plan, we actually got a behavioral change. And it was very obvious because these mice were moving all their body here. And it was a surprise, you know, the bodies were fine, but they had this pathological for brewing phenotype. And so that interests me know why, because it's an oddball. Here you have 39 genes all involved in making your body and this was interesting behavior. So we always kept that in my mind. And then I decided, this is the entry point where I'm going to find out, you know, why do HOX genes which control The behaviors?

Nick Jikomes 15:01

Yeah. And so for those who don't know, what are HOX genes and what, you know, what is their basic, most well established function,

Mario Capecchi 15:09

HOX genes, HOX genes a transcription factor, so that turning on and turning off genes, and they're, they're a very specific cluster of genes that are 39 of them. And it's true in mice, it's within humans. And they're involved essentially, in all aspects of making body plants. And they're used by all organisms, a multicellular organism to control their body plants, I mean, the first thing you decided is, you go from a ball to, to football, something much more. So you have now you have a dimension. Okay, and HOX genes are involved in setting up that axes. And they set up axes, you know, in all three dimensions, essentially, in the body, and then allow you to make sure that all of the parts of the body are the right place, and, and can connect up and then be functional. And, you know, and that's, you know, it's a fascinating group of genes. And very, I mean, they do amazing things, you know, just they were first discovered into South Florida, all of a sudden, an antenna would be coming out of your head, that's a function of a hot sheet that's responsible for that those operations. And just as far as developing gene targeting HOX genes would be discovered, and particularly that HOX genes, maybe were organisms that besides safflower. So the question was, okay, what are they doing advice. And so that's how we got into developmental biology. So we always have an entry point and an interest point. And then from there, we develop the conversation,

Nick Jikomes 16:51

I see. So So these HOX genes are involved in setting up the body plan, which sides the head, which sets the tail, wherever it's gonna go, what it's going to turn out to in terms of body parts. So normally, I'm guessing, you know, you delete a HOX gene, or you mess with the HOX gene, you get a body plan defect is in the wrong spot, it's

Mario Capecchi 17:10

very in a very particular region. So one HOX gene will be operating in this part of the chest, another one just below it, and another one above it. Okay, so, we always knew, for example, when we made hucks mutations, there will be something wrong with the body. And we would look at what particular part of the body and then see, okay, and see what's happening. Are they involved in limb development? Not only are they involved in the development, are they involved in making the fingers different? No, because that's changing in a book in the anterior posterior direction of the limb. Okay, so they're involved in literally in all those places, and I have to be able to do that. And then, but then we all of a sudden, so one, that it's called heartbeat that's involved, essentially, now in controlling behavior. And so then we got really interested in that aspect, but required us to change fields.

Nick Jikomes 18:09

So So you, you knocked out that gene, and you didn't see any body plan defects, it was only about it'll

Mario Capecchi 18:14

change, ya know, the body plans are normal. And then the only thing was that was apparent, was that a lot of hair was busy. And then that progresses, because these animals can't stop. They just keep on going.

Nick Jikomes 18:30

Interesting. And so that just that just triggers you to get into a new field. So it sounds like you're kind of always looking or waiting for an oddball like that, and that that's a new direction.

Mario Capecchi 18:41

Yeah, and then you have, you know, we have an entry point. And then and then we have to acquire new technologies in order to study in their terms. And therefore we get into optogenetics, we get into, no, we have little cameras that are smaller than the little finger, little fingernail, that we can insert into the brain. And then it can monitor cells moving around in the brain, particularly microglia. Because they may make them fluorescently, red or whatever color we want. So we can watch them and see where they are, and then activate them, for example, with the laser.

Nick Jikomes 19:17

Yeah, and so I mean, we've already we've already mentioned, you know, knockout technology. So this is, you know, technology that enables scientists to remove a genes or set segments of DNA. And when you take it away, you basically look to see what's broken, and then you can figure out what that gene is doing. So this is actually what you're probably most famous for. This is you the Nobel Prize in 2007 was given to you and a couple others for discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells. And this was the knockout gene technology. For the uninitiated, can you explain in basic terms, what does this technology do and how does it work?

Mario Capecchi 19:55

I mean, first you have to identify GE and you want to manipulate Oh, And we can make, you know, we can put it into a vector, which makes lots of it. And so then we can change it, literally change the sequence. And we can change one base pair or 10 base pairs or 1000s, of base pairs. And one of the first things you often do is simply delete a gene that has a sequence responsible for making that gene, and then see essentially, what the consequences as you mentioned, all of a sudden, your finger disappears. And we know we're in the program for making little finger. And it's, it's always that, you know, what you do is perturb the system, and then ask what the function what the function is determined by the perturbation you see. And, and that gives you a clue, essentially, what this gene is doing. And what was amazing in the beginning is, we are conscious concept of what genes which genes were doing what was completely wrong. I mean, nobody could predict what the consequences would be in the mouse, if you remove topspeed, seven, or eight or whatever. And then, but you always infer the function from what you see in any animal. And that gives you enormous power. And then once you identify the gene, then we can start changing it men we want, we can put in markers that for us, red, or green, or yellow, or whatever. And that that allows us to then follow those cells in the, in the live animal. And again, is the, you know, the technology is always in vivo, it's always in the live animal. Because we cannot really know even that today, we can we don't have the capability of studying complex phenomena, except in the animal itself, and do the perturbation in the animal, and then see what the consequences and then really realize what the function is. And I think it's, you know, it's up to the imagination, what you do with that, once you have the technology and you could do anything you want with it. There were 1000s of genes that we had no idea what they were doing. And the question was, you know, okay, which was easier to study, okay. And I decided, well, HOX genes would be a great entry point, because we know they do dramatic things into Safa flies. So the question is, are they doing similar things? And mammal and and then and then take the ball once you have it and run with it.

Nick Jikomes 22:36

In when you develop that technology? Was that work that you were doing in your lab at the University of Utah? And when was that happen?

Mario Capecchi 22:44

No, we started the project. I mean, I was thinking about the project just before coming to Utah. But we actually started all the work here. And I mean, this is sometimes you do science by serendipity, all of a sudden, you see something you didn't expect. But in this case, we actually planned it. I mean, I planned in the sense I knew what organism I wanted to do Bice and I knew what I wanted to do, I wanted to change genes, because there was no other way to do genetics in a mouse, and we into Safa, we can select for mutation. So because you can work with enormous numbers. In mice, we can work with large stoppers, but not enormous numbers, if nobody could afford it. And so there you have to use very different genetics, we couldn't utilize and look for the mutation, we have to create it. And it was obvious, we had to create it. And we had to be very specific, we didn't want to just bleed it, we wanted to be able to change specific nucleotides, so that we could have power to change the gene in any way we wanted. So often, you want to make more of the gene product rather than less of the gene product. And we're making it in a new area of the body that's normal, that gene doesn't function. So the all of those manipulations are doable by Gene targeting.

Nick Jikomes 24:06

And so what's the timeline here? When was this work happening? Like when did you

Mario Capecchi 24:10

know this is happening? I came to Utah at 73. And so I started feeling seriously probably in 75. And one of the first things you do when you want to do work is try to get a grant. So you submitted to NIH, and I thought it was very excited. They sent it back a very good study section. I actually knew who the people words actually personally knew some of them. And their response was impossible. Obviously, no money. And so they're you know, all of a sudden, you have a big question to do that. What are you going to do with that information? Are you gonna quit your new project? Or do you have the guts to actually continue that project? And I decided I would go for it. enormous risk four years later, if I'd failed I would be done. Okay, so yeah.

Nick Jikomes 25:03

Can you explain that piece? So you're trying to get funding to do this very exciting project, which we know now, you know, later turns into, you know, it's a Nobel worthy of line of work. But at the time, the people deciding whether or not to fund it, don't think it's feasible. They don't think it's possible, you could do this. So how did you actually do it? Did you already have some grant money and you just had,

Mario Capecchi 25:23

at that time, in that grant, I had three parts to dope, what's the one exciting part? They say, drop the exciting part and do the $2. So I took the money for the adult parts and used for Gene targeting.

Nick Jikomes 25:39

So if it wouldn't have worked, basically, it would have been screwed?

Mario Capecchi 25:42

Well, you know, 40 years later, would have nothing, because and then plus, it spent their money to do something they didn't advise.

Nick Jikomes 25:49

No, I mean, in the early days, your lab, you know, you, I don't know if you had tenure yet, or what, but what what was motivating you to take that type of risk.

Mario Capecchi 25:59

I did have tenure. But I think motivation is simply, you know, I made the assumption, and there wasn't any data to support it, that I knew that homologous recombination existed. Okay. And particularly in, for example, in my surname, at that time, both of Augustus homologous recombination was used for sex, it was used for chromosomes, that is you have a mother paternal copy of a maternal copy. And then you want to now make an individual, which has mixed use of those, that chromosome containing parts of one and the other, and the use of molecules recombination to generate that mixture. So that was what was known about homologous recombination. But I made the assumption that, that they would also utilize it in normal sex in what we call somatic cells, everything but germ cells. And then, if it was in somatic cells, then there it should be able to work and do what I wanted. Because the machinery is there, all I had to learn is, how does the machine you work? And then how does it How does it work the way I want it to work, that is to do things that I wanted, rather than what nature wants to do with it. And that's that's what the jump was, they didn't believe that what they argued was that the exogenous piece of DNA would never find the same sequence in the old genome, which is 3 billion base pairs. So, and I said, that machinery has might be there. And if it is, then it has to be able to utilize it in a workable fashion. And there was the frequency wouldn't be impossible. And so it was, it was a jumper century. In parts, you believe that? They said it just wouldn't work literally said it was impossible. And I said, I think we can make it work. And fortunately, four years later, he didn't have work. And I set the continuation Grantland, very same study section. And they said, We're glad you didn't follow our advice. So timing is important.

Nick Jikomes 28:21

And do you feel like, like in science today, that level of risk taking is possible? How much of it was like you and your own personality? How much of it was the environment, the general scientific environment? And is that type of risk taking possible today?

Mario Capecchi 28:36

It's still positive today since I'm still having grants triaged. And I said, literally, I said back on a note saying deja vu, it must be a pretty good idea, though, I think, you know, I think in science, you have to take risks, and he doesn't want to take risks. You know, they want to make sure that if he give you money, that you do something useful with it. And the risks don't allow you to do that. But I think in science, you have to do it somehow we have to still, we don't have a good system for getting that. So the risk has always been taken by the scientist. Right? And it should be the other way around. They shouldn't be strictly no boss should be taking risks. And, you know, in the English system does have that. What they do, if they think somebody is really good, we'll just support that person. Somebody like kendrew, works 25 years of trying to figure out the structure of a protein never published as a paper, then it works. And then they publish and they get the Nobel Prize. Okay, but they've been supporting them for 25 years, without, you know, requiring papers, but that doesn't happen in this country. And I think it's bad because I think we need both. I mean, you have to take risks in order to do really significant new stuff. And be in that position, I'd like to be working in an area where I don't feel crowded. And I'd have, you know, and I'm doing stuff that is highly risky. But I think if they, it works, there's a high payoff. And that's true of this project was anxiety. And we're doing, I'm having a terrible time getting flooded. And, you know, just battle. And that's a bug now, you know, I think it's working. And we're starting to publish papers on it, and then I think we'll be accepted.

Nick Jikomes 30:40

Yeah, how does, you know, you mentioned, you know, you can, you can, science can be set up in a way where you are supporting a promising individual, and not requiring them to publish papers every year to continue getting funded and doing their work. But today, in the US, especially, you know, the currency is papers, you're meant to publish your work in a peer reviewed journal and a good one. That, you know, that's the proof that you should be continued to be funded and do good work. If you're going to do it the other way, and you're going to just stop funding individuals and give them lots of time and space to do higher risk stuff. How do you actually do that? How do you actually identify who's worth support? And

Mario Capecchi 31:22

that's their, that's their risk? Yeah, you know, I'm sure that in England, scientists are being supported that eventually I productive. Okay, so it is a big risk, because you're continually pouring money, but you have to have the confidence that, you know, that that person. One is they have to explain what they're wanting to do in a logical manner that says it's possible. But on the other hand, you know, they know, it may take a long time before they're ready to publish. And it literally some of these projects do take 25 years, it's not in the five year bracket. I mean, we're all set up for doing everything every four years, because the fifth year you have to get renewed, but they were willing to take that risk. And I think at the cabinet, this lab in England was famous for that they have lots of people that they were supporting in that environment. And doing brilliantly in all areas can be Knology, you name it, crystallography, D, DNA structure, Watson, Crick, and so on. So I think it's my feeling is that, you know, obviously, if sometimes you fail, when you take risk, that's what risk how risk is defined, it asserts that there has to be some failures, but you have to be able to just swallow it, and know that the returns are gonna eventually be much greater than without doing that. But your NIH has never been willing to do that system, or the US has never been able to convince itself it shouldn't have that system.

Nick Jikomes 33:00

So it sounds like it's it's sort of always basically been this way in the US it has has the way that science, your science and your science generally, the way it's been funded and the way it's conducted, as it changed much in the US over the course of your career.

Mario Capecchi 33:13

No, it's always been tough. The only thing I always see is negative aspects of it that you know,

when when you can't get grants, because pretty much everybody's just dependent on NIH funding for doing medical research. So think, though, you just have to, I mean, literally right now, for example, it comes out of my retirement foot to the support of my lab. Okay, so that's, that's risky. Also, I burned through my money, like, all of this stuff is very expensive. And now we think it's getting cheaper and cheaper. But what's happening is actually skateboard more expensive, simply because now we have new tools that are very expensive. So it's, no, there's, there's no way to beat it. You just have to go along with it. And hope. And I think, you know, I'm sure there are failures, that people haven't gone through that. They they take a big risk of they don't make it and and nobody hears about it.

Nick Jikomes 34:20

And so, you know, you've been at Utah running your lab for decades. Now. What were you doing before that? What What was your PhD in your postdoc years, like that? Love to get there?

Mario Capecchi 34:31

Right. And that was all at Harvard. And it's fantastic. I mean, there's just at the beginning of molecular biology, literally when it's been born. And, and what made it work was for people coming in the influence from people in chemistry, biology, genetics, medicines, sewing, physics, you name it, all of them coming up there together, to be able to work on a new way of doing sights. And it was, you know, it was mind boggling. Because if you turn around and nothing was known a protein, how do you make a protein? That was my first project to figure out? How does protein synthesis start? How does it end? And and how does it continue looking, none of that was done. So all you could turn in any direction and find your a significant problem. And the other thing is, also was heavy was, you know, you could work something of a year or two, and then submit a paper to sell. Now, you know, you have to work over 10 years to get a paper needs to sell. So it's a very different, very different area and very different environment. And, but it was it was really fun, because it is, it was the beginning and brilliant minds from all over the world participating it. And you know, I read a paper somewhere before starting school at Harvard. It was by an air and very and put Polly and Polly feet. All of a sudden, wow. Now hearing we have the tools now to figure out the genetic code, and so on, so on, so forth. And similarly, regulation of genes was all jacked up in the novel, figuring out how genes are turned on, or turned off. And so it was heady. It was absolutely amazing.

Nick Jikomes 36:42

And so you started your lab in the 70s. So that your postdoc, your graduate school years, that must have been what the 1960s?

Mario Capecchi 36:49

Right. 61 This is when I started my graduate school. And then I jumped directly, I should have gone into a postdoc, but I jumped into a position at Harvard Medical School, right after being a graduate student.

Nick Jikomes 37:07

And so, so in grad school, is that when you were working on protein synthesis, right. And that was under Watson. Right? Right. Yeah. Once, and Watson has it, as in Watson and Crick, and Watson

Mario Capecchi 37:19

incorrect. It was, he was, is intuition was amazing. He wasn't, you know, he couldn't do experiments in a sense of using his hands. But he really believed his thought, you know, he thought about things, it could figure out how nature was doing stuff. And then, and then we did it. And he had a large slab and there was, no, he took care of me like, it was amazing. As a graduate student, I have a technician. So I was producing papers with 10 papers, I think as a graduate student.

Nick Jikomes 38:00

Yeah, just for those listening. That's yeah. So today, typically, you get one, maybe two, more than that would be considered remarkable.

Mario Capecchi 38:08

Right? That's right. So

Nick Jikomes 38:11

what was what was it like working for him? What was he like, his personality and just

Mario Capecchi 38:15

as a person, extremely, very intense, very supportive. And, and you could do anything you wanted? We would talk with him, and he kept getting us excited. And we kept going. And, you know, he would play tricks on us, it would set up dummy, or essentially, competitions saying, or this guy is working on something very similar, you know, nothing. Protein synthesis style with, you know, somebody's working just on our system. So you working electrical pretty crazy to make sure you're not second, because in science, unfortunately, second doesn't count. So, but, but on the other hand, nobody really goes you just friends with the other people. So, you know, we did they did they short, shared information, and and there were things which preceded that, I think, but I think, you know, the atmosphere was really gratifying and very exciting. And they were tough. I mean, I have both Wally Gilbert and Watson as a mentor, and they will shred us apart and give when we gave lab meetings, but the good thing is that then once you got into the real world, it was a piece of cake. So you had already gone through all of that. So I think actually, it's good. I mean, you know, at the time, we thought it was rough. But I think what the outcome is it does make you feel more secure.

Nick Jikomes 39:46

Yeah, I mean, you must have I mean, you were around in the soul, sort of the golden years of molecular biology be figuring out how the genetic code works, what the code is, how proteins are being made, all the stuff that we you know, we I guess we take for granted today that we You've known for a long time. I mean, you must have met so many amazing scientists like Crick, oh, yeah,

Mario Capecchi 40:08

he would come twice a year to the lab. You know, everybody, I mean, everybody knew everything he did. And he would travel, you know, the whole world that multiple times over here. So you knew every, all the other labs were doing, and as well as keeping up with yourself. So no, so it was in your knowing what the one thing you always learned is, the two brains are always better than one synergy is much better than competition. And I think that's a Google that's really worthwhile. Because, you know, often people think, oh, you know, I'm afraid of the competition. And even if you're working on the exact same stuff, you have different reasons for doing those experiments. So again, it's always synergy wins.

Nick Jikomes 40:56

And so that back then molecular biology is this new field, we're trying to understand how biological systems work at the molecular level at the level of DNA and proteins and things at net scale. But it was very, it was attracting people from all over. So it's like the new hot field, the ability to do these experiments and understand things at that level was unlocked by technological development. But it wasn't just biologists, you had people from physics and chemistry, everyone sort of converging in and that's part of what made it so exciting. Is there a field of science today and biology, generally speaking, that you think is like the the modern day molecular biology where you have that kind of confluence,

Mario Capecchi 41:39

I think the nearest thing is neuroscience. And again, it's getting in lots of people for computation, and into the field. And so another thing that's really healthy. So I think that's one of the reasons I'm in the field and why it's exciting to me. So I think, I think that's the nearest thing to, to those. And, you know, and until recently, the tools weren't there to resize. So, you know, people thought about it, that the tools weren't there. But now all of a sudden, they were there. They're coming in faster and faster. And so it's a, it's a very exciting area right now. I think, if I were a New Scientist, I would be going into North science at the beginning. Okay, so I think, and I don't know where the next step will be. I think neuroscience is that occupies for quite a while, simply because the complexities are enormous. I mean, they're staggering and in essence, and you know, because you're, you're working with billions of interactions in our brain, in millisecond timescales, where now for example, you go into a machine, and they tell you to think about an apple 15 minutes later, they can tell you where you're thinking about the apple. That's, we need to shorten that by six orders of magnitude. And in that process will be several Nobel Prizes. What can we simply look at what you can't do? And then that's where we're, you should be looking at, and and know that that's coming in. And I'm sure you know, that window will be shortened after milliseconds in 10, less or a year less years, even though now we look at as daunting and impossible.

Nick Jikomes 43:29

In before before you started your PhD? What like what were you doing in college? Were you doing science? Were you interested in science? How did you get when did you know that you wanted to go into research.

Mario Capecchi 43:41

As an undergraduate, I was actually a political science major for the first quarter. And I looked around and I couldn't find a science in political sciences, which the physics and from then on, it was just science. And then I switched essentially, molecular biology. Because I went to Antioch College, which has a work study program, and work floater, and you study a quarter, and it wasn't. And the jobs are all over the country, in the fields that you earn interest. So for example, I was working at MIT. And there, again, molecular biology just starting, and then all of a sudden you get into it. And I saw you know forget about physics and go into Bullock or biology. So that's when the switch occurring was just as a leader stages of my undergraduate work, but working in it, and I worked in Alex Seuss's lab and at MIT and what are the norms of mindset that a lot of fun.

Nick Jikomes 44:41

And so before that, where did you grow up as as a kid as a teenager?

Mario Capecchi 44:47

Let's have a look. So you I grew up in the streets of Italy during the war. So it was essentially I was a thief for my first five years. I'm getting my own food by ticking.

Nick Jikomes 45:04

So that was that's World War Two. Yeah, World War Two. And so so if you're in it, you're, you're from Italy as a child, as a child living there. Eventually you make it to the US and get educated here. When When did you first get to the United States?

Mario Capecchi 45:21

Well, my mother was, she was actually a poet. And she got her education at the Sorbonne in France, in Paris. And then she started pamphleteering against Nazism, fascism. And then things got very hot, and she knew she was going to be picked up. And so she moved up to the material of Italy. And then that's where the Gestapo came in and took her to Dachau. And at that time, she said, you know, you're going to be better off on your own than you are with me. And that was a wise decision. But a transition is lifted on a farm that she had provided funds for, to take care of me. But those funds ran out in the years. So then I was in the streets, from then on. But she survived darker, and took her when I was in 45. And took her over a year, almost two years to find me, because I was moving all the time. And then she found me and then she had a brother living in United States. So he sent money for a boat ride went to us in 1946.

Nick Jikomes 46:27

Wow. So you got to the US in 1946 is that New York,

Mario Capecchi 46:32

New York, right, those islands, spent the night looking at this statue of liberty and then proceeds through Ellis Island and then got on a car and drove to a commune. My uncle, who's a physicist, lived on a commune. And then the next day I went to school, I have never been to school before. Didn't know the language or anything. And proceeded. How old were you? Nine.

Nick Jikomes 47:03

Okay, so you got here at a pretty young age. I mean, it's just, it's just like in the history books. You You were at Ellis Island, you took a boat over the Atlantic? What was that? Do you remember that? What was that, like?

Mario Capecchi 47:18

Two weeks shipping across the ocean, it was a slow boat. And it was mostly all refugees, I think that were coming over. And, you know, before that, I'd had one hot meal in nine years. And then all of a sudden, you go into a situation where, you know, being and also, you know, no parents to then having 65 parents on a commune. But the transition was enormous. And, you know, and I was savage. I mean, I was, you know, I was a strict kid. And independent, didn't know how to interact with people that, you know, literally. So they said, You know, I would never learn how to read because I didn't know how to be in a school before. And so, but, you know, my aunt taught me how to read. And then it proceeded. And they, you know, they were so convinced that I could make it that they said, you know, this, you have to put them into a trade school, but the, they even had victory picked out the school, and so on and so forth. So, you know, the kids, what's amazing about kids is they don't question anything, but the situation is just what it is. It there's no right or wrong or anything associated with it. You simply exist in that situation that you're in, and if you're not, you know, I was smart. I mean, no, I would study people I've studied their behaviors and so on. So I know when the first of money didn't make any sense. I couldn't take money from a person if I go to a store and present them with money, they call the police when I get money so so you know, the your values are completely different. All that's important is food and shelter. And that's what you have to you have to figure out how to do that on a daily basis on your own each for

Nick Jikomes 49:30

so so you get to Ellis Island, you're living with your uncle and a bunch of other people you learn to read you don't start learning how to read until like the age of nine did you stay with English or Italian that they taught you?

Mario Capecchi 49:43

English everything from I wasn't allowed to speak any Italian they want to make the transition. They know that was a mistake. I think they should have maintained the argument in 10 languages of words if they want to, but they thought I would learn English quicker if I simply never saw it and again, better ergic still has 100% transition?

Nick Jikomes 50:03

How long did it take you approximately two, to learn to speak into read English?

Mario Capecchi 50:08

Probably three, four weeks. It's okay. So

Nick Jikomes 50:12

picked it up very quickly.

Mario Capecchi 50:14

Very quick, very quick.

Nick Jikomes 50:18

And then when you finally get into school, I mean, you must have gotten into school at some point, regular grade school. What was that like? And what were like, Were you a good student? Or did you not like school because of of your childhood? I

Mario Capecchi 50:31

think? Both. I mean, I think one is they simply said, Okay, you got your, because you ag your third grader. So that's where I started. And the teacher was really very good. She was amazingly good. When I first got there, she gave me a roll of butcher paper, this is a big rolls of paper that was just roll forever. And they were stumbling Holland, and she said painted murals. I mean, she communicated and was leaving was plenty to paint a mural about Colin, everything, you know, so when bales ice skating, like so and so forth, cheese, everything was in that mirror. And in that process, I didn't have to have languages English, but I was learning English as then, you know, as I started to students interacting, and so on. And so she provided an environment, which was friendly and encouraging. But at the same time to cognizant that it was going to take a little while. And so that's that worked. And then from then on, was a good student, I've always got good grades. But initially in that school, at kid Damia was frowned upon, there was a lot of tough kids coming from an army PeriK and so on that were at that school, and education was shoved upon, because you had to be there because you had to go to school. But they didn't. Nobody encouraged had so that nobody felt that it was a good thing to be doing. And then I'll switch from there in high school, to a prep school of Quaker Christmas, which was quite the opposite. That was a completely academic, and got you ready for college. And so I think that there was a very important in that transition that all of a sudden you solid power of education. But even then, you know, what was really important at that time, was sports, and women, girls, so those were the highlights, and but I still was getting good grades without doing any work. And so, you know, they all the letters would say, you know, you've got to concentrate, you've got to work on this, but so and so forth. But you know, a kid, that's what he enjoys, and I enjoyed school, which I was very good at wrestling. And also, even though it's very small, I played football, and then played soccer, and then play bliss baseball. So you know, year round was always sportsmanship sorts. And then when I went to college, I just switched on a dime. So now, I purposely went, I could have gone to sports scholarships. In wrestling, I was really good. But I went to school, they had no sports. And then just right there, I said, Okay, this is starting to get serious, and started academics, and then flourish there. And I know it was good, because a lot of the kids this was a heavy arc. But a lot of the kids were coming from Brown school sites in New York, and they were very good students, and I easily competed with them.

Nick Jikomes 53:51

So, you know, it sounds like you know, there's a lot of stuff in your early life that was outside of your control. You just had to adapt to it. Right? You had to separate from your mother you had to live, figure out how to live on your own. You had to suddenly go to America learn English and constantly put into these completely different contexts where you were just forced to adapt. Do you think that had anything to do with your style as a scientist?

Mario Capecchi 54:16

I think so. Yeah. And certainly also, the commune was also really important. I mean, I don't think I could have made that transition. You know, that biggest jumps isn't accepting that commune, where 65 people are all concerned with you, and in a social way. And so I think that was really important because when I first came in, I really was an animal. They just have to take me and they did it. You know, Quakers or money means nothing. Everything is service in the year abroad on the world, do something to make the world a better place. And I think and you're The education that is, is topmost, that was, that's the most important thing for you. And I think, you know, and again, and again, you know, shelter and being taken care of, and lots of activities for kids, I mean, enormous number of representatives, because, you know, we did all sorts of stuff, that, that weren't available to the kids outside. We would go into Philadelphia to the art museum and paint located anywhere else was doing that. So you're exposed to everything. And I think that was also quite meaningful. And then finally, you know, my uncle was superb. This is when he made the first micro microscope, using quantum mechanics, you know, when quantum mechanics was just being born, and participating that so, you know, and that background was extremely important, even though they didn't push everything? No, nobody ever yelled. Everything was very quiet and swings.

Nick Jikomes 56:07

And so, I mean, you're obviously able to adapt and assimilate once you got to America, and you started, you know, getting formal education and all this stuff. But you mentioned being a Feral Kid in Italy, what do you remember from from your years in Italy, when you were living on your own? What? What was that like? And what were you doing?

Mario Capecchi 56:26

Literally only sick about. And you know, and you'd go days without food. It's not that every day you had food, you know, you had to take opportunity of when you had it, and then eat. So that occupied you and all the time, 24 hours a day, essentially, because if you go three days, without food, then you started getting hungry. And I can now still, you know, I can go full five days without eating anything, not even thinking about it. So the body adjusts to whatever circumstances you're in. And what you think about it is what what will help Okay, for example, sometimes I've worked with another person, and sometimes I've worked alone. And then, and then if you find somebody that they click with, when two people are always better, because one can distract, and the other could do the operation. So two can always function a lot, but there's another separate but if you find somebody that works, then you stick with that person. And it's always about survival.

Nick Jikomes 57:31

And are you talking about stealing food? That's how you're getting?

Mario Capecchi 57:34

Oh, yeah, that's, that's the only way I got, nobody's gonna give me anything. They didn't have anything to discuss during war. So nobody ever, you know, I never thought about begging that would have been a waste of time. So it's always you take what you can. So in order to do that, you have to know the situation, you have to know the people there, you know, what's how they function? And then take advantage of that?

Nick Jikomes 57:59

And do you think, I mean, this probably forced you as a young child to be very perceptive to watch people to study their behavior and figure out what they're going to do next. You know,

Mario Capecchi 58:09

nothing that does, I mean, that does keep going. I mean, I think, my I use my senses a lot, particularly to visual senses. And so. And then in science, we see things that seem something is very bleep better than anything else you could think about in terms of sensory perception. But I think up and you use those eyes very well, when you train them. I think, you know, you learn to be essential to stick to it, to not be in a rush, you have to be patient, you have to study the situation. And then and because the people that didn't, didn't survive resources, it's the Darwinian principle taking place on the streets. And I survived. And I think I survived simply because I was good at what I was doing, and be able to care for it. And use my senses in a helpful way than in non productive way. How much?

Nick Jikomes 59:19

How much did you understand what was it like? Did you understand that there was a war going on? And did you understand, like, why your mother had to separate from you?

Mario Capecchi 59:28

Yeah. And at that time, you know, I knew I knew both German and Italian. So when the Gestapo came, I knew what the conversation was all about. So I knew exactly why she was going and where she was going, and that I'm likely not going to see him for a long time. I didn't know that was gonna be forever, but that was certainly a possibility. And then, and then I went to a wasn't a farm for almost a year of if we're not leaving that for good.

Nick Jikomes 1:00:00

What's, what's the earliest memory that you have?

Mario Capecchi 1:00:04

The earliest is actually wanting to stop a cane with to pick up my mother. I mean, I've actually seen where the farm that I was on, since then they actually flashed it on the newsfeed newspapers and so on. So then they had a picture of the house, and I recognize it, and they took me there. And they had actually the same family who was still there on the farm. And they still had all the papers from my mother, we've achieved a portrait so that she had left, they kept on the office on 60 years, and then gave them to me at that time. So I think those are the those are the recollections you see, but my first very my memories, so when they came, and it was clear that we're gonna take her away. So so

Nick Jikomes 1:00:58

for those years that you were living on the street, basically by yourself, and the wars going on, and you're separated from your mother? What like, Were you scared most of the time? Were you How did it feel just to be a kid on that environment? Yeah.

Mario Capecchi 1:01:11

Not new, not scared. Not you really concentrating and concentrating on food. And so I knew essentially, where all the farms were, I knew where their chickens were at know how to steal eggs. You know, you name it. I knew what, you know, what was guarding that farmers, usually big dogs. And so you have to be aware of that. And then but in the in the town, then it's all the street vendors and the small shops that were the your targets.

Nick Jikomes 1:01:43

It sort of sounds like you know, you're in this very precarious you know, dangerous situation. You're, you're a young kid on your own. But it sounds like you were very concentrated and motivated on survival on just getting food. Is it fair to say that this was you know, there was no learned helplessness, there was not a lot of anxiety, you were you were you were focused on survival. But you don't necessarily feel bad,

Mario Capecchi 1:02:07

right. And he also knew, you know, that in 10 to 12 days, you have to move on, because by that time, everybody knew who you were. But they will keep an eye on you rather than you keeping an eye on them. So they might have to move to a new village, a new town and keep progressing, going further and further south. During that whole period of time. That's why my mother couldn't figure out you know where it was. And she took it literally two years to find it.

Nick Jikomes 1:02:35

So when you when you first separated from your mother, and when you were a baby, what what part of Italy are you in?

Mario Capecchi 1:02:41

It's all Northern, all sensory from the T roll down to a city called or I guess it's a city, Reggio Emilia, which is just a little bit because they're on his biggest city there.

Nick Jikomes 1:03:00

And by the time you got to America, was the war still going on? Or how to end it.

Mario Capecchi 1:03:04

So she was liberated in 45. Then she picked me up in October of 46. And then she had to, she had to go to court to get custody. And my father fought the custody. But amazingly, in Italy, it's very paternal country. She wants she needed she didn't get custody. And then and then a week later, we're on the boat from Naples to New York. Why? Very quickly.

Nick Jikomes 1:03:43

I see. And did your mother stay in Italy? Or did she come to America as well? No, she

Mario Capecchi 1:03:47

couldn't with me. And your father, she never recovered. I mean, she never mentally recovered from Taco. So she, she really wasn't able to take care of me once we came to the United States. That's why my uncle or brother essentially

Nick Jikomes 1:04:06

took care of me. I see. And so did she ever talk about it about recovering?

Mario Capecchi 1:04:12

No. And I pushed. Yeah, that was relentless. But she would talk. She wouldn't have something. I've talked about it. A little dribbles, but not nothing significant.

Nick Jikomes 1:04:25

And what like why? So your parents weren't together? They were separated?

Mario Capecchi 1:04:29

Well, my father, my father's in Italy. They'd never got married. So there was a bit of fleeing, isn't she? And she was very smart. She didn't marry him. He's sort of a very black person. Not black, literally black, but not a wealthy person that took care of other people. Thought about itself. I have some air force. But that's not something you look up to.

Nick Jikomes 1:05:10

And so you get to America and it sounds like you adapt pretty quickly. And you learn the language and you're doing okay in school and all of this stuff. Like, like, Do you Do you recall those being? Was it exciting to go to America? Was it a happy time? Oh, good. You know,

Mario Capecchi 1:05:28

my nickname was cheerio, because I was always smiling. Everything was available on the album's that, you know, it was very funny. When I first got into my house, you know, in the middle of the night, I would get up and go down to the refrigerator and take stuff. And then one night, my uncle shows up as a hero. You don't have to see all the other stuff because you can have it as you want it. Okay,

Nick Jikomes 1:05:59

you weren't you weren't you were stealing food, you didn't need to steal just out of habit. What? When you're when you're on the streets of Italy, what was? What was the food that was most common? Or what was something that what was like? What was really exciting to get? What was your favorite thing to steal?

Mario Capecchi 1:06:17

I mean, everything you eat, it was right. And it's so because he didn't have any place to cook it. So you know, so it's always vegetables and fruits, and eggs. Eggs were probably you know, they were big. But, but they are also much rarer. You had to figure out where a chicken coop was, and then get it not having dogs get your instead. So so it was mostly just fruit and vegetables and the fruits, you know, I could get into trees, or I could climb trees and get whatever I wanted there. So answers was right. And I think I mean, where things got tough was in later winter, when there wasn't things that you could get outside. So then you have to get it from the, from the shopkeepers. And stuff that you could just run in with and then eat.

Nick Jikomes 1:07:18

Yeah, given given your early childhood, your relationship to food there, you know, you come to America, and it's completely different in different contexts with food. And also just like so thinking about food and diet and your you know, your early life history. And the fact that you know, you're still running a lab and you're still, you know, you're still you're still going, you know, all these years later. What's your relationship to diet today are you are very particular with your diet, are you

Mario Capecchi 1:07:45

very particular, and I'm a pathological exerciser. To the point I put in about four hours of exercise every day, what do you do? I run I do a cardiovascular I'd roll. And then I do wait.

Nick Jikomes 1:08:05

While you're still lifting, you're still lifting? Yeah. Oh, yeah. Oh, that's amazing. Yeah. You just have you always been that way. You've just always been athletic. Yeah. Yeah. Yeah. How do you How important do you think that's been just to give you like, the mental endurance to have such a long scientific career?

Mario Capecchi 1:08:24

So no, I think I think it's really important. I think this thing loves oxygen. So and that's exercise big shows that your heart is good enough to really pump away and give you the oxygen it needs. So it's a nine, I think exercise is extremely important. St. You just have to do it, and set aside the time to do it. And I think, you know, I get up at 430 in the two hours of exercise to them, and then they do two hours of exercise instead of eating lunch. So only two meals a day.

Nick Jikomes 1:09:00

As you do breakfast and dinner. Yeah. And what do you what do you like to eat? You said you were pretty disciplined about

Mario Capecchi 1:09:06

everything. I mean, I mean, I eat probably meat at most once a week and then and then some so on and so forth. And very careful to eat organic. And I think pesticides are really bad for you also think eat quality food and part of that should be green. So why don't eat I changed quite a bit, but just make sure I don't eat things I shouldn't be eating but you don't need a lot of sugar and you don't need a button love pasta. You know the one hot meal I ever had was actually pumpkin ravioli. So that was prepared essentially We have a football. Player, the only happy I've ever had was in English from age four, onward to nine.

Nick Jikomes 1:10:16

So, you know, thinking about, you know, just thinking, you know, you talked about how, basically, you know, your life history probably influenced your scientific style, in many ways, your ability to adapt to new situations, and just be willing to jump into new contexts and stuff.

Mario Capecchi 1:10:30

Even be self sufficient. I think that's a big part. I mean, we, you know, we could send out people to do sex tissue sectioning, for example, you know, but we do our own, because we look at the same slides much more carefully than he had any pathology would. So we really try to be selfish and, and do everything that's required, and acquire the new technology isn't needed to do it. And so, so you know, so that's what I like to do here in the lab to be really capable, you know, not be restricted by technology that is encompassed with technology, rather than ship it out somewhere, for something to be done. And in the process, you know, the reason I switched to that a physics is simply because physics was getting to be bigger and bigger machines and bigger picture groups, and I wanted something to do with my own hands. So rather than not than nothing, be relying on this enormous machine to be able to do get your data.

Nick Jikomes 1:11:39

And, you know, how, you know, has, you know, over the course of your scientific career in the United States, you know, going from your PhD through your postdoc to building and then and running your own lab? How has, you know, just across the entire field in biology and academia, generally, how has like scientific culture changed over the course of your career? Has it changed in drastic ways? Or is it mostly, you

Mario Capecchi 1:12:04

know, and what's also surprising is that each area, when I'm in developmental biology, or whether they're in cancer biology, the society associated with this is different. In some fields are much, much more open. In our in our curiosity, for example, is developmental biology was much more open than the other fields that it went into. And I would guess a big part of that is that women had a predominant role in developmental biology with going back to the beginning. So it's a different culture. And it affects it as a culture. And suddenly, so those things things, you see that actually, this not hear about, and we actually see them. And I think that now each each field has its own persona peculiarities, good points and bad points. In some fields are much more hustle than others. What are you doing in my terms?

Nick Jikomes 1:13:04

What do you think? What do you think determines that what makes you feel hostile?

Mario Capecchi 1:13:10

Fortunately, I think it's often the top leadership in that field that sets the tone. And I think if you have some people there, there are difficult, that's going to be a difficult field. They had an enormous influence. And so rather than whether it's the top people or more friendly, culture becomes really

Nick Jikomes 1:13:36

what I'm, you know, for, like a PhD student, or an aspiring scientists today, someone young at the beginning, you know, how would you, how would you advise them around how to develop a sense of what they want to study in what field to go into,

Mario Capecchi 1:13:52

I still, I still always say, go into the field that you're really passionate about. Because nobody can give you that passion. So you have to have it. And people have different reasons for passion, you know, the association, family members having canceled or whatever. And I think so to me, so, you know, science is really an individual enterprise. And it's really the people that make it. And so I think what you have to do, is really, you know, what, if you enjoy it and think about it, then you go to a tubular, that will do a good job. But if you don't, if it's not that integrated into your soul, then you're not going to do a good job. Because, you know, you never know when a good idea pops up, you know, pops up anywhere randomly, but if you're not thinking about it snuck up. So you have to be always thinking about it. It's 100% only, and it's you know, people say well, you know, I have a family of all these commitments and so on. Unfortunately, scientists 100% You really know, I think about it all the time. Little died up thinking about experiments. And I dream about experiments. It's very weird.

Nick Jikomes 1:15:19

And do you have a family yourself? Well, yeah. And what, what part of your career? Did you? Did you have children?

Mario Capecchi 1:15:30

I mean, well, she's, I was in the 30s sort of leadership on that not weigh up now early. And I think, then, you know, and my daughter, she was thinking about going to science. But then she also majored in the arts, and now she's in arts. And she's completely committed to art. And, you know, an art I think it's even harder than science. Because, you know, it's, it's at least in, you know, in science, the criteria for what's good, what works, what is, you know, has to be in reproducible, it's sort of self worth in art doesn't have that. So it's, you know, establishing what's good or

what's bad or is, you know, it's completely, it's almost arbitrary to human when it's the right credit, there are no set boundaries. So I find that art is much tougher than science. If you the objectivity is lost.

Nick Jikomes 1:16:39

If you hadn't gone into research into into being a scientist, what do you what do you think you would have done instead? That

Mario Capecchi 1:16:49

would be a wrestling coach.

Nick Jikomes 1:16:54

Wow. So you are. So you were good at wrestling? Even as a kid,

Mario Capecchi 1:16:57

though it was, it was really? No, I would have gone to any school in the country about personal scholarship.

Nick Jikomes 1:17:06

Did you? Did you learn how to wrestle on the streets of Italy? Did you have to fight? And no,

Mario Capecchi 1:17:11

I did not. But it didn't. But I didn't know. You know, you do learn things. I mean, I did have to protect my surf as though I was given. And when I came first United States, my first job was to take care of the upperclassmen, and beat up the upperclassmen that were bothered, and that was, okay. So I became the protector of the overall class. And I did a good job, because they had no idea what they were up against. So

Nick Jikomes 1:17:51

what do you think, you know, what do you think the risks and benefits of of going into academia and staying in academia today are for a scientist, a young scientist, compared to when you got into things,

Mario Capecchi 1:18:04

I think it's much tougher. The bands on a single paper is just astronomical. And I think, you know, they should do away with supplementary data, it is awful, because it means that the paper never has an end, they could always ask for when stuck in Supplementary Data. So I think that makes a huge difference. And I've been spending a huge amount of time on a single paper isn't very productive. And I think it's not productive for the person, when they get more data, more data, but they're not learning new things. They're just repeating things and regurgitating things that people say, Okay, this should be included, or that should include when often nobody even looks at the Supplementary Data, we just meet the main text of the paper. And that's it. And here, normally, when 10 pages to a page, supplementary, 30 pages. It's out of scale. And I think it's very bad for science and the students, particularly the students, because they should get, you know, they should get a variety of experience when they're graduate students, they should be working on one or two papers, they should be thinking a lot about stuff, and then that will really start building now what are they going to do next? And they don't have time to do that. By the time they finish postdoc often is doing the same stuff they were doing as a graduate student. And that's, that's awful. You know, I urge all of my students graduate students to do go to a post a completely different field, see what they are doing, see what the tools are utilizing. And then at the end, you can choose whatever you want. But broaden your experience as I think, you know, the broader your experience, the more open your mind is to new things. And network quenching that we make enforcing, enforcing just to concentrate on one problem. What's,

Nick Jikomes 1:20:05

what's your opinion on the way that the peer review process for publishing papers and biology works today?

Mario Capecchi 1:20:14

I think it's the only system that I can think of such works. So it has to be, I mean, anything else, if there was an executive committee, I think it would be much worse. So I think it has to be a peer review. I think it is abused. I think sometimes, you know, people have self interest and, and voicing. And that's a travesty. But, you know, there's still, you know, it's still by far the best system we have. And even, you know, our own system, I think, again, is superior simply because it's not a pyramid. And there isn't one guy at the top controlling funds for anything below. Each individual has a capability of submitting a grant, and getting the money and doing what they want. And that's almost unique to United States. I mean, it's, it's perfect, it's stupid to know, all the other countries that are much more pyramid structure. So, you know, so you know, I complain, but it's still by far the best. So it was a cake playing too loud. But you can't try to improve it. And I think right now, we need it to get broader in acceptance of risk. I mean, I think we have to make risk of part of our journey, and simply accept it, and then sometimes you're not gonna get returns. And that should be part of the money. They know that they're going to waste some money. But I think they'll gain much, much more than what they lose. So I think because right now, we're just, it's, I mean, I literally, that's the you know, every time I've submitted, they always say, Oh, the investigators, blah, blah, blah, and then they give you their money. And then it's catch 22, they want you to do the stuff before you do the experiment that you're trying to get the money for. So without any money, what it happens every time and I can't do it daily. It's really awful. And I think they should be have a little bit of leeway. You know, the best predictor of the future. Now only predicting the future is the past. Something else. And so I think you should give much more credence than they currently. If you if you want if the goal was to be productive productivity, what do you think their goal should be to people, as well as being merely going for the unexpected? Because that's where jobs really make a difference.

Nick Jikomes 1:23:10

What do you think about the part of peer review? Where what what do you think about the fact that, you know, the reviewers always know the identity of the people submitting the paper, but the reviewers are Anonymous.

Mario Capecchi 1:23:23

Anonymous? I don't mind that. I mean, I think I think people will, if it wasn't, you know, they knew they'd be much more guarded as to what they say. I mean, I think, you know, you should learn from the process. Now, if I get I love, critique, I love critique. I mean, if somebody if I give somebody a paper, and they say, it's terrific, there's nothing you haven't learned anything. Okay? But if they say, No, you know, this is really foggy, you know, read, really rip it apart, then then you have something to go on, and to change it and make a difference. So, you know, we should almost want criticism, criticism is vital to science. But on the other hand, I don't mind not knowing who it is, if I don't want him to be, you know, to be good. And I want him to be. And I want him to be critical. They see something I don't see well, so fantastic.

Nick Jikomes 1:24:26

What do you what are you most excited about in your science? And that's going to happen in the next few years? Are you excited that you might be able to make some major breakthroughs when it comes to understanding the neurobiology of OCD and anxiety? And if so, like, where do you think you'll be in terms of the discoveries 234 years from now?

Mario Capecchi 1:24:45

And I'm hoping that three of them have the whole neural circuit searching for microglia, who they taught me to starting the process, all the way to the end of the behavior. And the cute thing we've just done now is we can induced the behavior, and now see my cochlear reacting. Okay, so we can see both ends of the spectrum can see we can tweak microglia. And that gives rise to behavior, we can tweak behavior and see microglia reacting. And now we have to fill in all those steps in between an hour. I hope to do that right away. And I'm setting up to be able to do that. Because I think, you know, we don't have, particularly with behavior, we have no knowledge of that. I mean, it is a zebra, you know, so. And, you know, the other aspect of it is that depending on where I'm in the brain, the outputs different. In order to hit here, we hit grooving, and we do it there we get anxiety, we do it. Play seek, we can get both.

Nick Jikomes 1:25:49

So we have which parts of the brain are you talking about? We're

Mario Capecchi 1:25:53

going we're going into prefrontal cortex, we're going into DMS, and then we're going into the big. Okay, so of different cultural places in the brain. And so then so then you'll have to develop the circuitry in each of those places. And even which neurons are the first responders? So they're different in different regions? Because the outputs are different, so on? Or is it the signals are different whether whether you know, so, because we have multiple channels, we'll be able to get all of that all of that information will come out. And, and all the tools to do it are now, five years from now, we couldn't even think about these experiments. Now. Now, all of a sudden, they're, they're good. And we can do it. So I think it's a it's an amazing time. And I think we'll have you know, and the other thing we found, I don't I don't know, if I mentioned that, that the two populations of cells or two populations of microglia, they do opposite things. So that's, you know, why is that? What makes one be functional? So accelerated? Was the function so break at the molecular level, we'll be able to define that is to know that

Nick Jikomes 1:27:17

is that's the mystery. The two populations of microglia one, you know, there's this functional difference in terms of the output you see at the level of behavior, do you understand anything yet, in terms of markers that differentiate them, or you know, aspects of

Mario Capecchi 1:27:30

it, we only have marker specific marker for one of the populations. So that's been, and I'd like to have the gene that's responsible for the other population, we don't know. And we'd love we'd love to have that. Because hopefully, the other Hoecker is always, you know, the nature doesn't use a gene, just for one thing, we use it for lots of different things. So there may be pleiotropy. So it may not there may not exist, a unique gene in the other population, for example, that specifies that population, that that gene may be doing other things in other cells. So and so we were sort of lucky that ours was specific, and gives the market because there's no way right now we have sort of a market on it. And because we have the only marker that you can use to look at that population. So, um, but we, you know, we send it to Jack so that, you know, other people can get it if they want it. But at this point, I think there's so much to be done with it. That's going to be really informative. And what it's what, you know, what's gonna get me excited is when I get a surprise that says, This is what how it works. And I'm sure it's going to be a surprise in the SERPs because nobody knows how it works. But it may be a real surprise, in the sense that a mechanism is used, nobody ever dissipated would be used for that purpose. So

Nick Jikomes 1:29:08

Is that Is that your favorite part of the scientific process? When when there's something totally surprising that comes out? Yeah.

Mario Capecchi 1:29:15

That's always that's real quick, because, you know, you know that, you know, the one I didn't know but as you know, I thought I knew

that nature was utilizing modeling as recombination for something useful. But then all of a sudden when you see that the actually does that. Wow. And so there's a big difference between thinking and knowing that it's, that's the way it goes. But then what spurs you on the other day and gives you important information to keep going.

Nick Jikomes 1:29:52

And are you? Are you still to do still take graduate students in your ladders?

Mario Capecchi 1:29:57

Yep, no, that's not what visibly hustling nowadays. I'll tell you a story I wanted to have and when I was still an undergraduate, as if you're in my shoes, where would you go? At that time, there were only three choices that MIT Caltech, Harvard that he looked at me, and he said, it could be fucking crazy go anywhere else. So I did that was persuasive.

Nick Jikomes 1:30:39

And what's, uh, what's the how do you how do you mentor your PhD students as opposed to your postdoc? So what's what's your how's your approach different for the two groups?

Mario Capecchi 1:30:52

Right, you know, the real risky stuff, about the most risky stuff, I do myself, the next lower level of risk a gift to graduate students. And postdocs, as soon as they come in to steal, they're thinking about jobs. So they don't want risk. So there is that gradation. So you'd make it so you do make those choices. And I think, I mean, I think the, the rules are different in the sense that in a posting, what you're preparing them to, is to run a lab. That's when you want them. And I know, when they're ready, for example, is when they really start confronting me. And arguing with me, and that's good, that's a healthy site. And I want him to do that. No work. But that that's how you decide, you know, where are they? At? What level of development? Are they, you know, are they ready. And I think sizes are there now. So they have to be tough. So I think you have to build that toughness, and, you know, get him over the humps in most of the time in science, you do stuff, and it doesn't work, or you think it doesn't work, actually, it's actually, I learned more from the failures that I did for the turbine support. But and they should have been, and should set it up to be, not only know that it failed, but know, have enough controls to know why it failed, and then be able to change it to make it work. So I think, you know, it's those kinds of things that they have to really on a daily basis be able to do to be able to carry on, and know that they can get done no matter what they particularly know that one criteria, I still use a say can meet you do this, if nature can do it, I know we can be done. And that's a huge, huge thing. Because with, with Gene targeting, at the beginning, we didn't even know whether we were going in the right direction, you know, you might be falling asleep. And that may be a completely misleading direction to go. So you have to, you know, have a rope set up to say, you know, you're proceeding in the right mode, and know that if this experiment works with the next period, but you know, in this initially it's random, and you have to look for signals. And then if you find a signal, then it's can we make it better given a bigger big noise, small errors, in essence. So I think that those are the things you have to teach them and incorporate it, because it's going to be different. It's not going to be easy. But I think it's just as exciting because it's so much to learn. I mean, we're still naive, we really, particularly in terms of how this thing's working. All we know is it's really good machine.

Nick Jikomes 1:34:03

In terms of you know, other than the intellectual side of things, you know, being able to think about problems and being able, and also just the experiments themselves being able to do experiments, other than those things, which are very important, what are some of the most important skills that a scientist needs to be able to develop to, to actually run a lab

Mario Capecchi 1:34:25

presentation, and then writing and then finally working with people, because it's the people enterprise. And none of those two, we get a really good training. I mean, you're all assumed that you somehow pick it up by osmosis. But, you know, and all of those are really important. And I think if you can't communicate your science, you're lost. You're completely so you have to learn how to give talks and and be comfortable with it and enjoy it. anticipate what questions you're going to get rather than just waiting. There never be surprised. I always tell us by Austin's, you know more about this field than anybody else in the audience. Relax. And welcome, particularly a person question.

Nick Jikomes 1:35:22

Well, Mario, I want to be respectful of your time. Is there anything? Are there any final thoughts you want to leave people with related to, to your career and your story or anything that we talked about today?

Mario Capecchi 1:35:35

Thank you. I mean, one is that science is that sometimes people, you know, degrade essentially Science in the Public. And I think science has created a lot of problems that were also the solution to global warming is going to be solved by scientists periodically. I mean, it's not they're going to do, they're going to develop this tools to be able to do something about it. And obviously, the money has to come, it's going to be huge, and what comes from elsewhere. But, you know, our dependency on science is even greater now than it ever was. So I think people have to take science seriously welcome it encouraging. Because without it, we're just gonna go down to two, new, we're getting close. One sub, one of the aspects of humans, is they almost have to go to the brink, before they get even interested, you know, almost falling off the cliff. But we will science and will need even much more science that is currently being put into the pipeline. So I think, you know, I think anything that encouraged the science is a good thing. I mean, I don't believe there's anything bad comes out of science, I think if science can be misused. But that's a very different thing. From the site's being, we should be able to go out and find anything, doesn't matter what the information is the problem. It's utilization of that information. So I think it's, that's a very different enterprise. So we should encourage all science to see what that tells us. And then and then go with it. And, but rather than be timid, and bow, our face is just too slow. And I think we need to really just sparked up the activity as opposed to getting up and desperation. What there's a saying, I think that when things get tough, you have to work harder. It's it's not a time to sit back, it's a time to actually put in even more effort. So I think that, to me, has been important. And so that requires, you know, it's it is it's an economic thing, you have to decide what your priorities are, and then go for it. But, but science will be the salvation, that has to be happy, it won't happen without it. And that's true, whether we're talking about medicine, medicine, and global warming isn't huge. It's really big. And I think people are just beginning to even think about it, rather than embracing it and saying, This is what we should be doing and what resources and what if what we spend now, it's trivial to work we're gonna spend in the future. The longer we sit back, the more expensive it is. And fast and it's not going to be it's not going to be 10 years from now. It's going to be tomorrow. So I think there's urgency, and there's need. And certainly, you know, I don't want to scare away people from science. That's, I mean, I think it is tougher, but I think it's but it's also, you know, you can do so much more. So I think one thing that I always do is I try to, you know, even though they're going to have a tough time, I encourage students to go into suppliers, saying, you know, this is a bad guy. Whether it, you know, pull into it make a difference. So, I think we have to really, we encourage students, I think that's an important message. All right, that tells me, it's a fun. There's nothing like it. People pay us to play. How can you beat that? So I think it's so important.

Nick Jikomes 1:39:56

All right, well, Dr. Mario Capecchi thank you again for your time. This was really fun. Thank you. Thank you. And I look forward to seeing what discoveries come up next.

Mario Capecchi 1:40:06

Terrific. I'm hoping it lasts. I'm pretty excited


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